Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide hormone which is normally present in the circulation at concentrations similar to angiotensin II (Ang II) and is primarily derived from angiotensin I (Ang I) by tissue peptidases, including neprilysin, thimet oligopeptidase and prolyl endopeptidase (Ferrario, C. M. et al., Hypertension, 1997, 30:535-541) and by angiotensin converting enzyme (ACE) 2 from angiotensin II (Ang II) (Vickers, C., et al., J. Biol. Chem., 2002, 277:14836-14843). In addition, Ang-(1-7) is a substrate for ACE (Chappell, M. C. et al. Hypertension, 1998, 31:362-367). ACE catalyzes the conversion of angiotensin I (Ang I) to the biologically active peptide angiotensin II [Ang II]. Treatment of patients or animals with ACE inhibitors results in a significant elevation in the circulating and tissue levels of Ang II, as well as the N-terminal heptapeptide fragment of Ang II, angiotensin-(1-7) (Campbell, M. C. et al., Hypertension, 1993, 22:513-522; Kohara, K. et al., Hypertension, 1991, 17:131-138Lawrence, A. C. et al., J. Hypertens., 1990, 8:715-724;and Luque, M. et al., J. Hypertens., 1996, 14:799-805). It has been suggested that ACE inhibition not only elevates Ang-(1-7) by increasing Ang I, the substrate for Ang-(1-7) production, but also by preventing Ang-(1-7) conversion to the inactive fragment Ang-(1-5).
Although Ang-(1-7) was long-considered an inactive product of the degradation of Ang II, studies showed that the heptapeptide produces unique physiological responses which are often opposite to those of the well-recognized angiotensin peptide, Ang II (Ferrario, C. M. et al., Hypertension, 1997, 30:535-541). Thus, Ang-(1-7) has been shown to stimulate vasopressin release from neuropeptidergic neurons (Schiavone, M. T. et al., Proc. Natl. Acad. Sci. USA, 1988, 85:4095-4098), increase the release of certain neurotransmitters (Ambuhl, P. et al., Regul. Pept., 1992, 38:111-120), reduce blood pressure in hypertensive dogs and rats (Benter, I. F. et al., Am J. Physiol. Heart Circ. Physiol., 1995, 269:H313-H319;and Nakamoto, H. et al., Hypertension, 1995, 25:796-802), and have biphasic effects on renal fluid absorption (DelliPizzi, A. et al., Br. J. Pharmacol., 1994, 111:1-3; DelliPizzi, A. et al., Pharmacologist, 34, 1992; Garcia, N. H. and Garbin, J. L., J. Am. Soc. Nephrol., 1994, 5:1133-1138; Handa, R. K. et al., Am. J. Physiol., 1996, 270:F141-F147;and Hilchey, S. D. and Bell-Quilley, C. P., Hypertension, 1995, 25:1238-1244).
Besides its role in reducing blood pressure, Ang-(1-7) attenuates vascular growth both in vitro and in vivo (Freeman, E. J. et al., Hypertension, 1996, 28:104-108; Strawn, W. B. et al., Hypertension, 1999, 33:207-211;and Tallant, E. A. et al., Hypertension, 1999, 34:950-957). Also, hypertensive patients administered ACE inhibitors show a reduced risk of cancer, particularly lung and sex-specific cancers (Jick, H., et al., Lancet, 1997, 349:525-528; Lever, A. F. et al., Lancet, 1998, 352:179-184;and Pahor, M. et al., Am. J. Hypertens., 1996, 9:695-699).
What is needed in cancer prevention and therapeutics is a way to prevent tumors from forming, or to inhibit the growth of tumors once formed. Also, what is needed are agents that act specifically at the tumor cell, thus minimizing non-specific and/or toxic side effects. Preferably, the chemotherapeutic agents will comprise ligands that target the chemotherapeutic agent to cancer cells with high efficacy to either reduce cellular signals that promote cell growth, or to increase cellular signals that promote cell death.